The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Interleukin-8 (IL-8), also known as neutrophil chemotactic factor, is mainly produced by macrophages and epithelial cells, and has known to play a key role in immune system by recruiting immune cells (e.g., neutrophils) to the infection site. Recently, interest has been growing on identifying the relationship between the tumor-produced IL-8 and development of the tumor, especially in tumor metastasis and mechanism of immune-suppression in the tumor microenvironment. For example, several studies found that tumor-produced IL-8 is highly expressed in metastatic tumor cells and indeed, is capable of induce epithelial-mesenchymal transition of the tumor cells to produce tumor-initiating cells (e.g., tumor stem cells). Other studies showed that tumor-produced IL-8 attracts Myeloid-Derived Suppressor Cells (MDSC), which can provide immune-suppressive microenvironment around the tumor by interfering T-cell mediated immune response in the tumor microenvironment.
In order to mitigating the effect of IL-8 in tumor development, efforts had been put to neutralize tumor-expressed or endogenous IL-8 by providing human or humanized antibody against IL-8, anti-sense oligonucleotides or microRNA against IL-8. For example, U.S. Pat. Pub. No. 2003/0068319 to Bar-Eli discloses inhibition of angiogenesis and metastasis of tumor by fully humanized and isolated monoclonal or polyclonal IL-8. In another example, U.S. Pat. No. 5,849,903 to Petrzkowski teaches 20 base pair-length anti-sense oligonucleotide against IL-8 effective to reduce growth of melanoma or lung carcinoma. However, the effect of anti-sense oligonucleotides or microRNA may vary depending on the type of tumor, and the delivery method of such compositions. Also, isolated human or humanized antibody may not be effective in some tumor microenvironment where the isolated human or humanized antibodies are cleaved by endogenous metalloprotease in the tumor microenvironment.
Thus, even though several approaches of inhibiting expression or activity of IL-8 in tumor microenvironment have been studied, targeting IL-8 using recombinant IL-8 antibody or single chain variable fragment (scFv) with amino acid sequences of high affinity to IL-8 has remained largely unexplored. Therefore, there is still a need for improved compositions, methods for and uses of recombinant IL-8 antibody or single chain variable fragment (scFv) to target tumor-expressed or endogenous IL-8 in the tumor microenvironment to promote effect of cancer therapy.